In spite of the anticoagulant drugs such as warfarin, heparin, aspirin and clopidogrel, thrombotic diseases still remain to be the leading cause of death in developed countries [J. Med. Chem. 2007, 50, 5339]. Thrombosis formed in the arterial circulation system can cause acute myocardial infarction or ischemic stroke, and deep venous thrombosis formed in the venous circulation system can cause diseases such as chronic lower limb pain and pulmonary embolism. It is estimated that 100,000 people die of deep venous thrombosis and pulmonary embolism each year merely in the United States [J. Med. Chem. 2010, 53, 5339].
The existing antithrombotic drugs are divided into antiplatelet drugs, anticlotting drugs and fibrinolytic drugs. Among them, anticlotting drugs are the main contents of antithrombosis treatment, which drugs are mainly thrombin inhibitors and vitamin K antagonists. Thrombin inhibitors represented by heparin and low molecular weight heparin have disadvantages such as ineffective oral administration, non-selective inhibition and high bleeding risk. Although vitamin K antagonists represented by warfarin can be taken orally. They also have the disadvantages such as small treatment index, high bleeding risk, and etc.
Activated serine protease factor Xa (FXa) plays a central role in the coagulation cascade system by catalyzing the conversion of prothrombin to thrombin. Thrombin has multiple coagulation functions, which include converting fibrinogen to fibrin, activating platelets, activating other coagulation factors, amplifying the function of FXa, and so on. Inhibition of FXa does not affect the activity of the existing thrombin, which can reduce the risk of bleeding, improve safety, and thus better than the direct thrombin inhibitor. Therefore, FXa inhibitors have become an important area for the research and development of new anticoagulant (thrombus) drugs, wherein their representative drugs, rivaroxaban and apixaban, have been sold on market, while some other drugs are in the stage of clinical research [Drugs, 2011, 7(12), 1503; Current Topics in Medicinal Chemistry, 2010, 10, 257-269; Nature Reviews, 2011, 10, 61].